Processes for Making Opioids Including 14-Hydroxycodeinone and 14-hydroxymorphinone
Improved processes for making opioid products having low impurity levels including making 14-hydroxycodeinone and 14-hydroxymorphinone from thebaine and oripavine, respectively.
1 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
a. dissolving thebaine in a carboxylic acid to form a reaction mixture;
b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and
c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition,
wherein the composition contains less than about 1000 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 1000 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.
2 . The process of claim 1 , wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid and propionic acid.
3 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
a. dissolving thebaine in a carboxylic acid to form a reaction mixture;
b. adding at least one strong acid to the reaction mixture;
c. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and
d. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition.
4 . The process of claim 3 , wherein the strong acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, methanesulfonic acid, trifluroacetic acid or mixtures thereof.
5 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
a. dissolving thebaine in a carboxylic acid and a solvent to form a reaction mixture;
b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and
c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition.
6 . The process of claim 5 , wherein the alcohol solvent is an alcohol.
7 . The process of claim 6 , wherein the alcohol is selected from the group consisting of methanol, ethanol, and propanol.
8 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
a. dissolving thebaine in a carboxylic acid to form a reaction mixture;
b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ;
c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition; and
d. adding a solvent to the reaction mixture.
9 . The process of claims 1 , 3 , 5 and 8 further comprising the step of purifying the 14-hydroxycodeinone composition.
10 . The process of claim 9 , wherein the purification step comprises reducing an amount of at least one of 8β,14-dihydroxy-7,8-dihydrocodeinone and 8β,14-dihydroxy-7,8-dihydrocodeinone isomer in the composition.
11 . The process of claim 10 , wherein the amount of 8β,14-dihydroxy-7,8-dihydrocodeinone is less than about 50 ppm and the amount of 8β,14-dihydroxy-7,8-dihydrocodeinone isomer is less than about 125 ppm in the composition.
12 . The process of claim 10 , wherein the purification step comprises the steps of:
a. dissolving the composition in a solvent to form a mixture;
b. distilling the mixture while adding a second solvent to the mixture; and
c. cooling the mixture to crystallize at least a portion of the 14-hydroxycodeinone.
13 . The process of claim 12 , wherein the other solvent is dichloromethane.
14 . The process of claim 13 , wherein the second solvent is an alcohol or acetonitrile.
15 . The process of claim 14 , wherein the alcohol is ethanol or methanol.
16 . A 14-hydroxycodeinone composition wherein the composition is greater than 91 percent (area, HPLC) pure 14-hydroxycodeinone and wherein the composition comprises less than about 45 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone.
17 . A 14-hydroxymorphinone composition wherein the composition is greater than 95 percent (area, HPLC) pure 14-hydroxymorphinone.
18 . An oxycodone free base composition wherein the composition comprises less than about 200 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 10 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.
19 . An oxycodone hydrochloride composition wherein the composition comprises less than about 25 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 10 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.
20 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
a. dissolving oripavine in a carboxylic acid to form a reaction mixture;
b. adding at least one strong acid to the reaction mixture;
c. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and
d. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition.
21 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
a. dissolving oripavine in a carboxylic acid and a solvent to form a reaction mixture;
b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and
c. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition.
22 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
a. dissolving oripavine in a carboxylic acid to form a reaction mixture;
b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ;
c. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition; and
d. adding a solvent to the reaction mixture.
23 . The process of any one of claims 20 - 22 further comprising the step of purifying the 14-hydroxymorphinone composition.
24 . The process of claim 23 , wherein the purification step comprises the steps of:
a. dissolving the composition in a solvent to form a mixture;
b. distilling the mixture while adding a second solvent to the mixture; and
c. cooling the mixture to crystallize at least a portion of the 14-hydroxymorphinone.
25 . An oxymorphone free base composition having at least a 99.9 percent (area, HPLC) purity made by the process as recited in claim 23 and further comprising the step of converting the 14-hydroxymorphinone to the free base composition.
26 . An oxymorphone hydrochloride composition having at least a 99.9 percent (area, HPLC) purity and comprising less than 5 ppm 14-hydroxymorphinone.
27 . The oxymorphone hydrochloride composition of claim 26 made by the process as recited in claim 23 and further comprising at least one step of converting the 14-hydroxymorphinone to the oxymorphone hydrochloride composition.
28 . (canceled)
29 . The composition of claim 16 , wherein the composition comprises less than about 30 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.
30 . The composition of claim 16 , wherein the composition is greater than 99 percent (area, HPLC) pure 14-hydroxycodeinone.
31 . The composition of claim 30 , wherein the composition comprises less than about 45 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 110 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.